TY - JOUR
T1 - An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy
AU - Thiele, Nikki A.
AU - Brown, Victoria
AU - Kelly, James M.
AU - Amor-Coarasa, Alejandro
AU - Jermilova, Una
AU - MacMillan, Samantha N.
AU - Nikolopoulou, Anastasia
AU - Ponnala, Shashikanth
AU - Ramogida, Caterina F.
AU - Robertson, Andrew K.H.
AU - Rodríguez-Rodríguez, Cristina
AU - Schaffer, Paul
AU - Williams, Clarence
AU - Babich, John W.
AU - Radchenko, Valery
AU - Wilson, Justin J.
N1 - Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2017/11/13
Y1 - 2017/11/13
N2 - The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.
AB - The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.
KW - actinium
KW - cancer
KW - chelates
KW - macrocycles
KW - radiopharmaceuticals
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U2 - 10.1002/anie.201709532
DO - 10.1002/anie.201709532
M3 - Article
C2 - 28963750
AN - SCOPUS:85031428200
SN - 1433-7851
VL - 56
SP - 14712
EP - 14717
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 46
ER -